Non-steroidal anti-inflammatory drugs (NSAIDs) are prototypical agents for treatment of inflammatory conditions. NSAIDs may also have utility as therapeutic agents against many forms of cancers. Reviewed in K. Kashfi, Anti-Inflammatory Agents as Cancer Therapeutics, pp. 31-89 in Contemporary Aspects of Biomedical Research: Drug Discovery, Advances in Pharmacol., S. Enna and M. Williams (ed.), 2009, vol. 57, Elsevier, Inc. Long-term use of NSAIDs, however, may lead to serious side effects including gastrointestinal and renal side effects.
Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H2S) can increase mucosal defense mechanisms has led to the development of NO- and H2S-releasing NSAIDs with increased safety profiles. NO-NSAIDs and HS-NSAIDs, however, have several drawbacks. HS-NSAIDs, for example, have relatively high IC50s for cell growth inhibition. Some NO-NSAIDs can form quinone methide intermediates, raising doubts about the role of NO in their biological activity. Other NO-NSAIDs have high IC50s for cell growth inhibition.
We have discovered that hybrid dual action compounds that incorporate both NO and H2S donor components are more potent therapeutic agents than compounds that donate only one of these groups. Such dual action compounds provide improved safety and methods of treatment of inflammatory conditions, such as cancers.